Why is history important?

1. History,Ethnicity, Medicine and Genes: Implication of genomics for community screening and prevention, the case of Ashkenazi Jewish Populations.

2. Why is history important? • Genomics is a science of populations and their diseases. It allows us to understand how disease, history and culture interact • It enables us to design rational screening and surveillance programs • It enables us to target specific populations and diseases, achieve wide-scale prevention, and avoid cultural and situational barriers to implementation of screening and prevention programs

3. Ideal population for genomic studies • Homogenous, genetically isolated over many generations • Traced to known ancestors or specific small ancestral populations • Accepts and supports genetic research • Geographic proximity to academic resources

4. Ideal populations • Icelanders • Amish • French Canadians • Ashkenazi Jews Ashkenazi populations support and welcome medical research, live in close proximity to major research centers and a substantial proportion of research scientists are of Ashkenazi origin and a part of the communities which they study.

5. Every ethnic group has its own genetic burden • Many of the methods that are now being applied to diverse populations were pioneered in the study of Ashkenazi genetics. • Many advances that intermingle history and medicine

6. Y Chromosome Bears Witness to Story of the Jewish Diaspora By NICHOLAS WADEMay 9, 2000 With a new technique based on the male or Y chromosome, biologists have traced the diaspora of Jewish populations from the dispersals that began in 586 B.C. to the modern communities of Europe and the Middle East. The analysis provides genetic witness that these communities have, to a remarkable extent, retained their biological identity separate from their host populations, evidence of relatively little intermarriage or conversion into Judaism over the centuries. Another finding, paradoxical but unsurprising, is that by the yardstick of the Y chromosome, the world's Jewish communities closely resemble not only each other but also Palestinians, Syrians and Lebanese, suggesting that all are descended from a common ancestral population that inhabited the Middle East some four thousand years ago.

7. Gene causes Parkinson's in Ashkenazim Although Parkinson's disease has not generally been regarded as genetic in origin, researchers at Yeshiva University's Einstein College of Medicine and Beth Israel Medical Center in New York have discovered a single gene that is the "major cause" of Parkinson's in Ashkenazi Jews. The report appears as "Correspondence" in the January 26 issue of the prestigious New England Journal of Medicine.

8. NEJM, Volume 354:424-425January 26, 2006LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews LRRK2 G2019S as a Cause of Parkinson's Disease in North African Arabs

9. The Lindex – A Pioneering Database • Jacob Jay Lindenthal, Ph.D., Dr. PH, Professor,Department of Psychiatry, Director of Public Medical Education,University of Medicine and Dentistry-New Jersey Medical School • focuses on North American Jews and consists of approximately 2,400 entries derived from over 1000 studies involving 574 diseases and conditions and classified according to the International Classification of Diseases (ICD-9CM). The database allows for review of each disease via literary form, as well as permitting manipulation of the data from the studies so that investigators can examine relationships among diseases. • Available through the library

10. Genes, Self and Group Identity We all have multiple identity We maintain Complex relationships A species is divided into races when it can be regarded as an essentially discontinuous set of individuals. Jonathan Marks

11. "Despite their long-term residence in different countries -- most Jewish populations were not significantly different from one another at the genetic level.” (M.F. Hammer, Proc. Nat'l Academy of Science, May 9, 2000) Some cases are easy DNA Testing to Determine “Native American Identity” DNA Analysis and the Cultural Affiliation of the Kennewick Man Black Southern African Bantu-speaking population who assert Jewish ancestry: Who gets to decide who is a member of the group?

12. Genes and History Genetic Diseases

13. Brief review of History

14. History Lesson - What happened in 70 CE • 2nd Jewish Temple in Jerusalem destroyed in 70AD • dispersal +++, to Europe = Ashkenazim • to Spain / Portugal = Sephardim • To other countries of the Middle East - Jews of Arab lands • 2,000 years, mixing of populations between communities – communal records ebb and flow of populations in each community

15. Simple genetic markers of populations • The Blood Group story • more complex genetic markers - DNA • ‘Jewish genetic diseases’ • Mitochondrial DNA

16. What does Tay-Sachs tell us? • carried and passed on amongst Ashkenazi Jews • origins in eastern Europe • not found amongst native eastern Europeans or Sephardic populations • must have arisen after Jews moved to Europe • Started in Western Hungary

17. The Tay-Sachs Story • in Jews of Polish and Russian origin Tay-Sachs carrier frequency is 0.0324 (1 in 31) • no carriers were found amongst near Eastern Jews dating these genetic changes to before 1100 when Jewish migration into Poland & Russia occurred • Jews from Austria, Hungary & Czechoslovakia twice as likely to be Tay-Sachs carriers than those with Polish or Russian origin • indicates a central rather than eastern European origin • difficult to distinguish the causes and influences • population bottleneck effects encourage genetic drift versus a potential selective advantage.

18. Illness ‘Inherited Tay-Sachs Gaucher’s disease Niemann-Pick Dysautonomia Canavan’s Disease Bloom’s syndrome, Fanconi’s Anemia Factor XI deficiency Mucolipidosis type IV Familial breast and ovarian cancer Hereditory NonPolyposis Colon Cancer and conditions common in Sephardim: Familial Mediterranean Fever, thalassaemia, G6PD deficiency

19. What happened in eastern Europe?

20. How did Ashkenazim inherit Tay-Sachs? • not from Adam or Eve • Jews in the pale of Settlement from 1264 • since then repeated cycles of growth, • variable population loss and migration • ‘ideal environment’ for some genes to • reach high frequency • founder effect, genetic drift + endogamy • strong evolutionary pressures • but perhaps also selective pressures

21. What selection pressures may have acted? = random effect • genetic drift • founder effect • selective advantage c.f. the Pilgrim fathers c.f. sickle cell anaemia

22. Genetic Drift • Random fluctuations in the frequency of the appearance of a gene in a small isolated population, presumably owing to chance rather than natural selection. • The effective size of the Ashkenazi population has been estimated by Risch et al. (1995) to have been as small as several thousand people about 500 years ago

23. Evidence in Support of a Founder Effect • Jewish religious & cultural practices • marrying within - endogamy • creates multiple genetically isolated population groups • does not create genetic diseases • but increases recessive gene concentration and expression of recessive conditions • this is an ideal environment for founders • multiple isolated settlements, multiple founders, many opportunities to concentrate genes • multiple examples apart from Tay-Sachs

24. What selective pressures might have acted? • Ashkenazi Jews subject to cycles of political & social upheaval • Matchmaking ethos - scholars married the wealthy and the elite • villages were lost in pogroms whilst others were forced to emigrate • subjected to natural selective pressures – oppression. • epidemics of plague, TB & starvation over-crowded & confined to ghettos • carrying some gene(s) may confer a survival benefit

25. Evidence for Selective Pressure • Average IQ in Ahskenazic (not Sefardic) populations is 112 - 115 • Visual Spatial scores are lower and incidence of myopia higher than surrounding populations • Consistent with 40 generations of narrow sense heritability (each 1 point increase n IQ of parents leads to a 0.3 point increase in the IQ of children)

26. Balance of Evidence Selective Advantage Founder Effect + Random Genetic Drift

27. The origin of Ashkenazis.

28. Ashkenazim Jews of Arab Lands Where do Jews fit?

29. Genetic evolutionary tree Russians Armenians Turks Poles Iraqi Jews Byelorussians Portuguese North African Jews Spaniards Muslim Kurds Kurdish Jews North Africans Ashkenazi Jews Jordanians Lebanese Palestinians Syrians Bedouin

30. Genetic Analysis of Populations • DNA markers • Cohen and Levi genes • History, Ethnicity and Health

31. Cohanim and their Genes • the priests of the Temple • responsibility to bless the Jewish community • tradition passed by fathers to sons • very stringent family / marital rules • ‘Cohen’ families descended from Aaron, the High Priest? • Y-borne tradition

32. Cohanim and their Genes • Goldstein & Bradman, UCL London • gathered DNA samples from priests - ‘the Cohanim’ • genetic markers indicate a common genetic origin • regardless of which post-Temple community group but approaches 100% in some communities • consistent with descent from one ancestral Y chromosome

33. Levite Genes • Levites (c.f. Levy) = assistants to the priests • similarly passed father to son • more heterogeneous, more mixed • less strict religious gate-keeping • common Ashkenazi pattern • Mr.Levy@eastern Europe.shtetl.com is ancestor for >50% Ashkenazi Levites • Mitochondrial DNA suggests Levites stem from 4 unique women on the maternal side (?European, ?Middle Eastern)

34. Summary • Jews are heterogeneous, but not random • more in common than people realise • documented history reflected in their genes • a large & complex extended family • no single ‘Jewish’ gene • Relevant to understanding and impacting genetic illness

35. Mendelian Disorders in Ashkenazi Bloom SyndromeCanavan DiseaseCystic FibrosisFactor XI DeficiencyFamilial Dysautonomia (Riley-Day syndrome)Fanconi AnemiaGaucher DiseaseMucolipidosis IVNiemann-Pick DiseaseNon-Classical Adrenal HyperplasiaNonsyndromic Hearing LossTay-Sachs DiseaseTorsion Dystonia Cancer Predisposition Genes Breast Cancer (BRCA1 and BRCA2)Familial Colon Cancer

36. Clinical Issues and Screening

45. Estimated Risk in BRCA Mutation Carriers – by Age 70

46. Males with BRCA Mutation • Risk of breast cancer – 10% • BRCA II – increases prostate cancer risk • May increase risk of colon cancer • Hereditary non-polyposis colon cancer gene is also higher in the Ashkenazi population • Can pass BRCA without being affected –skip generations • Some correlation of BRCA with Fanconi anemia

47. Non-Jewish Populatons with BRCA